Spatial transcriptomics landscape of lesions from non-communicable inflammatory skin diseases.

Abundant heterogeneous immune cells infiltrate lesions in chronic inflammatory diseases and characterization of these cells is needed to distinguish disease-promoting from bystander immune cells. Here, we investigate the landscape of non-communicable inflammatory skin diseases (ncISD) by spatial transcriptomics resulting in a large repository of 62,000 spatially defined human cutaneous transcriptomes from 31 patients. Despite the expected immune cell infiltration, we observe rather low numbers of pathogenic disease promoting cytokine transcripts (IFNG, IL13 and IL17A), i.e. >125 times less compared to the mean expression of all other genes over lesional skin sections. Nevertheless, cytokine expression is limited to lesional skin and presented in a disease-specific pattern. Leveraging a density-based spatial clustering method, we identify specific responder gene signatures in direct proximity of cytokines, and confirm that detected cytokine transcripts initiate amplification cascades of up to thousands of specific responder transcripts forming localized epidermal clusters. Thus, within the abundant and heterogeneous infiltrates of ncISD, only a low number of cytokine transcripts and their translated proteins promote disease by initiating an inflammatory amplification cascade in their local microenvironment.

[Differential diagnosis of common nail disorders in childhood]. / Differenzialdiagnose häufiger Nagelveränderungen im Kindesalter.

BACKGROUND: Correct diagnosis of nail changes in childhood may be challenging. Knowing the anatomy of the nail apparatus and some pathophysiologic principles helps to categorize nail disorders correctly. OBJECTIVES: This article gives a structured overview of nail disorders in childhood, thus, facilitating correct diagnosis of nail abnormalities in childhood. MATERIALS AND METHODS: A review of literature and our own experience are presented. RESULTS: In the first part we present fundamental anatomical characteristics of the nail apparatus based on embryonal development of the nails. In the main part we categorize nail disorders according to clinical presentation: transient nail changes, congenital nail abnormalities, infectious diseases of the nails, nail changes in the context of chronic inflammatory skin diseases, pigmented nail changes, tumors and nail changes due to trauma.

So close, and yet so far away: The dichotomy of the specific immune response and inflammation in psoriasis and atopic dermatitis.

Characterization of the complex interplay between cytokines, chemokines and microorganisms has led to a better understanding of the pathogenesis of both psoriasis and AD and resulted in new therapeutics targeting distinct immune responses. Psoriasis and AD share many characteristics: they are highly prevalent, chronic, cause primarily skin inflammation, but are associated with comorbidities, and come with a devastating quality of life due to itch and stigmatization. However, the pathogenesis of psoriasis and AD is opposing - psoriasis is dominated by a Th17 immune response that causes neutrophil migration, induction of innate immunity and exaggerated epithelial metabolism. Leading cytokines of this Th17 immune response are IL-17A and F, IL-22 and TNF-a. AD is characterized by Th2 immunity characterized by the signature cytokines IL-4 and IL-13 leading to an impaired epidermal barrier, dampened innate immunity and eosinophil migration. This review compares genetics, microbiome and T-cell infiltrate and resulting epithelial response in psoriasis and AD. Whilst the antagonistic course of psoriasis and AD is confirmed by response to specific biologics targeting the key cytokines of inflammation in psoriasis and AD, respectively, clinically overlapping phenotypes are challenging in our daily clinical practice. We conclude this review by summarizing what is known about these mixed phenotypes and how the identification of clinically relevant endotypes and molecular-driven decision-making is the next step in the field of dermato-immunology.

Is the humoral immunity dispensable for the pathogenesis of psoriasis?

BACKGROUND: Imbalances of T-cell subsets are hallmarks of disease-specific inflammation in psoriasis. However, the relevance of B cells for psoriasis remains poorly investigated. OBJECTIVE: To analyse the role of B cells and immunoglobulins for the disease-specific immunology of psoriasis. METHODS: We characterized B-cell subsets and immunoglobulin levels in untreated psoriasis patients (n = 37) and compared them to healthy controls (n = 20) as well as to psoriasis patients under disease-controlling systemic treatment (n = 28). B-cell subsets were analysed following the flow cytometric gating strategy based on the surface markers CD24, CD38 and CD138. Moreover, immunofluorescence stainings were used to detect IgA in psoriatic skin. RESULTS: We found significantly increased levels of IgA in the serum of treatment-naïve psoriasis patients correlating with disease score. However, IgA was only observed in dermal vessels of skin sections. Concerning B-cell subsets, we only found a moderately positive correlation of CD138+ plasma cells with IgA levels and disease score in treatment-naïve psoriasis patients. Confirming our hypothesis that psoriasis can develop in the absence of functional humoral immunity, we investigated a patient who suffered concomitantly from both psoriasis and a hereditary common variable immune defect (CVID) characterized by a lack of B cells and immunoglobulins. We detected variants in three of the 13 described genes of CVID and a so far undescribed variant in the ligand of the TNFRSF13B receptor leading to disturbed B-cell maturation and antibody production. However, this patient showed typical psoriasis regarding clinical presentation, histology or T-cell infiltrate. Finally, in a group of psoriasis patients under systemic treatment, neither did IgA levels drop nor did plasma cells correlate with IgA levels and disease score. CONCLUSION: B-cell alterations might rather be an epiphenomenal finding in psoriasis with a clear dominance of T cells over shifts in B-cell subsets.

[Personalized medicine in the field of inflammatory skin diseases]. / Personalisierte Medizin im Bereich entzündlicher Hauterkrankungen.

BACKGROUND: For sufficient treatment of patients with chronic inflammatory skin diseases, new concepts need to be established and biomarkers must be identified. OBJECTIVE: Presentation of new markers, their quality and implications for the clinical daily routine. MATERIAL AND METHODS: This article presents a discussion of basic research and a review of current achievements of personalized medicine in the area of chronic inflammatory skin diseases. RESULTS: Promising biomarker for the various entities of chronic inflammatory skin diseases have been proposed; however, they need to be prospectively validated and translated into affordable and feasible tests. CONCLUSION: There is still a long way to go to establish personalized medicine in the field of chronic inflammatory skin diseases and its success is dependent on multicenter collaboration to validate and implement novel biomarkers.

Prevalence and predictors of persistent post-surgical opioid use: a prospective observational cohort study.

Post-surgical opioid prescribing intended for the short-term management of acute pain may lead to long-term opioid use. This study was undertaken to determine the prevalence of persistent post-surgical opioid use and patient-related factors associated with post-surgical opioid use. One thousand and thirteen opioid-naïve patients awaiting elective surgery in a tertiary private hospital in Sydney were enrolled. Preoperatively, patients completed a questionnaire comprising potential predictors of persistent post-surgical opioid use. Patients underwent surgery with routine perioperative care, and were followed up at 90 to 120 days after surgery to determine opioid use. Factors associated with opioid use were assessed with logistic regression. We had an overall response rate of 95.8% (n=970) of patients, of whom 10.5% (n=102) continued to use opioids at >90 days after surgery. On surgical subtype analysis, the prevalence of persistent opioid use was 23.6% after spinal surgery, and 13.7% after orthopaedic surgery. Four factors were independently associated with persistent post-surgical opioid use in a multivariate model: having orthopaedic (odds ratio [OR] 4.6, 95% confidence interval [CI] 2.0 to 10.8, P <0.001) or spinal surgery (OR 4.0, 95% CI 1.7 to 9.2, P <0.001), anxiety (OR 2.1, 95% CI 1.1 to 4.1, P=0.03), attending pre-admission clinic (OR 3.7, 95% CI 1.6 to 8.6, P=0.002), and higher self-reported pain score at >90 days after surgery (P <0.001). More than 10% of opioid-naïve patients undergoing elective surgery experience persistent post-surgical opioid use. Identification of factors associated with persistent post-surgical opioid use may allow development of a risk stratification tool to predict those at highest risk.

Addiction: an underestimated problem in psoriasis health care.

BACKGROUND: Psoriasis is a disease of enormous socio-economic impact. Despite approval of numerous highly efficient and costly therapies, a minor proportion of severely affected patients actually receives sufficient treatment. OBJECTIVE: To investigate whether addictions are associated with psoriasis and to develop evidence-based recommendations for dermatologists in their daily clinical practice in order to improve medical assessment of psoriasis and patients' quality of life. PATIENTS AND METHODS: Psoriasis patients at the University Department of Dermatology were asked to fill out a paper-based self-reported anonymous questionnaire with 92 questions of validated screening tests for the six most common addictions in Germany (alcohol, nicotine, drugs and illegal drugs, gambling, food). Body weight and height as well as current Psoriasis Area and Severity Index (PASI) were documented as well. RESULTS: Between October 2015 and February 2016, 102 patients (65 males, 37 females; mean age 49.7 years (SD 13.4), range 18-83 years) participated in the study. Fifty-seven of the 102 patients showed addictive behaviour. Of these, 23.8% were high-risk drinkers, 41% regular smokers, 11% at risk of drug abuse, 4.1% at risk of food dependency and 19% compulsive gamblers. Compared with the general population, these results are significantly higher for alcohol abuse (P < 0.005), nicotine (P < 0.001) and gambling (P < 0.001). Body mass index was significantly higher in the study population (P < 0.001). CONCLUSION: Addictions and gambling are more prevalent in patients with psoriasis compared with the general population. Respective screening measures are recommended in daily practice for doctors treating psoriasis patients, and PeakPASI is suggested as a score to document patients' lifetime highest PASI. Parallel to new drug approvals and even more detailed insights into the pathomechanism of psoriasis, public health strategies and interdisciplinary approaches are essential for a general sustained psoriasis treatment.

Hypoxia induces apelin expression in human adipocytes.

Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. A modular incubator chamber was used to create a hypoxic tissue culture environment (defined as 1% O(2), 94% N, and 5% CO(2)). In addition, hypoxic conditions were mimicked by using CoCl(2). The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1α. In our study, we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1α.

Multifactorial anticancer effects of digalloyl-resveratrol encompass apoptosis, cell-cycle arrest, and inhibition of lymphendothelial gap formation in vitro.

BACKGROUND: Digalloyl-resveratrol (di-GA) is a synthetic compound aimed to combine the biological effects of the plant polyhydroxy phenols gallic acid and resveratrol, which are both radical scavengers and cyclooxygenase inhibitors exhibiting anticancer activity. Their broad spectrum of activities may probably be due to adjacent free hydroxyl groups. METHODS: Protein activation and expression were analysed by western blotting, deoxyribonucleoside triphosphate levels by HPLC, ribonucleotide reductase activity by (14)C-cytidine incorporation into nascent DNA and cell-cycle distribution by FACS. Apoptosis was measured by Hoechst 33258/propidium iodide double staining of nuclear chromatin and the formation of gaps into the lymphendothelial barrier in a three-dimensional co-culture model consisting of MCF-7 tumour cell spheroids and human lymphendothelial monolayers. RESULTS: In HL-60 leukaemia cells, di-GA activated caspase 3 and dose-dependently induced apoptosis. It further inhibited cell-cycle progression in the G1 phase by four different mechanisms: rapid downregulation of cyclin D1, induction of Chk2 with simultaneous downregulation of Cdc25A, induction of the Cdk-inhibitor p21(Cip/Waf) and inhibition of ribonucleotide reductase activity resulting in reduced dCTP and dTTP levels. Furthermore, di-GA inhibited the generation of lymphendothelial gaps by cancer cell spheroid-secreted lipoxygenase metabolites. Lymphendothelial gaps, adjacent to tumour bulks, can be considered as gates facilitating metastatic spread. CONCLUSION: These data show that di-GA exhibits three distinct anticancer activities: induction of apoptosis, cell-cycle arrest and disruption of cancer cell-induced lymphendothelial disintegration.

Implications of the situated learning model for teaching and learning nursing research.

Situated learning theory is gaining increased attention in the fields of human cognition and learning. The authors discuss the key researchers and basic assumptions of situated learning, and outline implications for the design and development of instruction. The authors describe how they applied the situated model to teaching and learning nursing research, an area identified as problematic for staff, administrators, and educators. They describe their personal observations and discuss feedback from participants at the workshop. The authors conclude that the situated model is useful for exposing nurses with little prior research experience to this domain of knowledge.

[Retroequatorial myopexy combined with bimedial recession for near-distance disparity esotropia]. / Behandlung der Esotropie mit akkommodativem und nichtakkommodativem Konvergenzexzess. Fadenoperation mit beidseitiger Medialisrücklagerung.

PURPOSE: In cases of esotropia combined with a high AC/A ratio, partly accommodative convergence excess or with nonaccommodative convergence excess, two methods of surgical therapy are possible: recession of the medial recti (Parks) and retroequatorial myopexy (Cüppers). Our aim was to answer the question whether retroequatorial myopexy alone and in combination with bimedial recession are appropriate methods of reducing the strabismic angle at near and distant fixation to values under 10 PD and near-distance disparity to less than 10 PD to form the basis for single binocular vision without bifocals. PATIENTS AND METHODS: Eighty-three patients, aged 2-14 years (39 boys and 44 girls), were included in the study: 37 children (group A) with early-onset near-distance esotropia of 14-48 PD for distance and 26-65 PD for near objects and 46 children (group B) with acquired near-distance esotropia of 8-45 PD for distance and 26-70 PD for near objects. Inclusion criteria were a near-distanced disparity of at least 10 PD (range 10-33 PD), a follow-up of at least 3 months (median 5 months, range 3-69 months), retinoscopy in cycloplegia and full refractive correction. The amount of conventional surgery was chiefly based on the distance angle of esotropia. The myopexy was placed 12, 13 and 14 mm behind the insertion of the medial rectus. RESULTS: In 73 of 83 patients (88%) we were able to reduce the strabismic angle for distance and near fixation to less than 10 PD and in 73 cases even under 5 PD. In 77 of 83 patients (93%) the near-distance disparity was reduced to less than 10 PD and in 72 patients (87%) even under 5 PD. Postoperatively, 9 children had bifocals, but 3 of them have meanwhile discarded them. Two cases were slightly ocvercorrected and 1 case undercorrected. Seventy children (84%) attained grade of binocularity. CONCLUSION: Retroequatorial myopexy (fadenoperation) alone and combined with bimedial recession is an effective procedure in treating esotropia with abnormal near-distance disparity.

Stereopsis after primary in-the-bag posterior chamber implantation in children.

PURPOSE: The purpose of this study was to evaluate visual acuity and binocular function after primary posterior chamber intraocular lens (IOL) implantation in children. PATIENTS AND METHODS: A retrospective chart review of 39 eyes of 31 children was performed. Fifteen eyes with traumatic, 17 with developmental, and 7 with congenital cataracts without any other ophthalmologic problems were examined before and after cataract surgery (irrigation/aspiration procedure with implantation of a posterior chamber IOL). Twelve eyes also received a posterior capsulorrhexis and anterior vitrectomy. The mean age at surgery was 6.9 +/- 3 years (range, 3-12 years). RESULTS: Twenty (51%) of 39 eyes achieved a best-corrected postoperative visual acuity of 20/40 or better (range, 20/200-20/20). The mean postoperative visual acuity was 20/40 in the traumatic and developmental cataract groups and 20/100 in the congenital cataract group. There was a positive correlation between cataract morphology and visual acuity (P<.05). Bilateral cataracts had a better postoperative visual acuity than unilateral cataracts (P <.005). Nineteen (70%) of 27 eyes in which no primary posterior capsulorrhexis had been performed had posterior capsule opacification. Stereopsis was found in 10 of the 31 patients: 43% of the traumatic cataract group, 30% of the developmental cataract group, and 14% of the congenital cataract group. CONCLUSIONS: After capsular bag-fixated IOL, visual acuity and binocular function in children older than 3 years were favorable and the complication rate, excluding posterior capsule opacification, was low.

Domain analysis of supervillin, an F-actin bundling plasma membrane protein with functional nuclear localization signals.

A growing number of actin-associated membrane proteins have been implicated in motile processes, adhesive interactions, and signal transduction to the cell nucleus. We report here that supervillin, an F-actin binding protein originally isolated from bovine neutrophil plasma membranes, contains functional nuclear targeting signals and localizes at or near vinculin-containing focal adhesion plaques in COS7-2 and CV1 cells. Overexpression of full-length supervillin in these cells disrupts the integrity of focal adhesion plaques and results in increased levels of F-actin and vinculin. Localization studies of chimeric proteins containing supervillin sequences fused with the enhanced green fluorescent protein indicate that: (1) the amino terminus promotes F-actin binding, targeting to focal adhesions, and limited nuclear localization; (2) the dominant nuclear targeting signal is in the center of the protein; and (3) the carboxy-terminal villin/gelsolin homology domain of supervillin does not, by itself, bind tightly to the actin cytoskeleton in vivo. Overexpression of chimeras containing both the amino-terminal F-actin binding site(s) and the dominant nuclear targeting signal results in the formation of large nuclear bundles containing F-actin, supervillin, and lamin. These results suggest that supervillin may contribute to cytoarchitecture in the nucleus, as well as at the plasma membrane.

[Threshold value retinopathy of prematurity. Visual outcome of 2-year-old children after cryocoagulation]. / Schwellenwert-Frühgeborenen-Retinopathie. Visusergebnisse zweijähriger Kinder nach Kryokoagulation.

BACKGROUND: The results of the Cryo-ROP group showed that cryotherapy significantly reduces the rate of adverse morphological and functional outcome of eyes with threshold retinopathy of prematurity. Structural status and visual acuity of 48 eyes which consecutively underwent cryocoagulation in our hospital between 1990 and 1994 were examined at 2 years corrected gestational age. METHOD: Visual acuity and fundus morphology were examined by Teller acuity-cards test, retinoscopy, orthoptic status and fundus examination. A favourable grating acuity was defined as > or = 2.2 cy/degree, a favourable morphology as no pathological or mild findings at the level of the posterior pole or stage 4 a. RESULTS: Fifty-six % of cases reached a quantifiable grating acuity between 0.32 and 13.0 cy/degree, 42% reached a favourable functional outcome, and 69% of the eyes had a morphologically favourable outcome. Fifty-five % of the measurable eyes were myopic, and 29% had a high myopia > or = -6.0 D. 47% showed a heterotropia. CONCLUSIONS: Our results show a discrepancy between morphological and functional outcome. Especially for zone 1 eyes, cryocoagulation of the avascular retina does not seem to allow a favourable morphological and functional outcome.

[Capsular sack-fixed IOL implantation in pediatric cataract. Visual prognosis and complications]. / Kapselsack-fixierte IOL-Implantation bei der kindlichen Katarakt. Visusprognose und Komplikationen.

BACKGROUND: The aim of the study was to evaluate results of visual acuity and binocularity and complications after cataract surgery with primary capsular bag-fixated IOL implantation in children. MATERIALS AND METHODS: Thirty-three children [mean age (+/- SEM) 6.9 +/- 2.9 years, range 3-12 years] accounting for 43 eyes, were examined before and after surgery (15 traumatic, 19 developmental, and 9 congenital cataracts, of the latter two groups 9 unilateral and 19 bilateral cataracts). RESULTS: All eyes had a best corrected postoperative visual acuity of 0.5 +/- 0.05. The postoperative visual acuity of the traumatic cataracts was 0.6 +/- 0.07, of the developmental cataracts 0.5 +/- 0.07, and of the congenital cataracts 0.2 +/- 0.05. Of the 43 eyes, 17 (40%) showed a best corrected visual acuity of 0.5 or better. There was a positive correlation between morphology (lamellar versus subcapsular opacification) and visual acuity (0.7 +/- 0.07 versus 0.5 +/- 0.05; P < 0.05). Bilateral cataracts had a better postoperative visual acuity than unilateral cataracts (0.7 +/- 0.07 versus 0.2 +/- 0.05 P< 0.001) Stereopis was found postoperatively in 62% of the children. In one eye a capsular bag-fixated IOL implantation was not possible, and so the IOL was inserted in the sulcus. Four children presented with postoperative fibrin formation. Posterior capsule opacification occurred in 19% of the eyes in which a primary posterior capsulotomy had been performed. CONCLUSIONS: The prognosis of visual acuity and the results of stereopsis in children older than 3 years following capsular bag-fixated IOL implantation are very good. Both the intraoperative and postoperative complication rates were low.